Dr. Shisheva joined
Wayne State University in 1996 with the ambition
to discover new molecular players in her
life-long field of scientific interest – the
mechanism of insulin-regulated glucose
transport. Immediately upon setting her lab, she
embarked on a risky expedition searching for
genes selectively expressed in adipose and fat
tissue. This effort paid off by the isolation of
an exceedingly large evolutionarily-conserved
enzyme. Dr. Shisheva called it PIKfyve (for PhosphoInositide
Kinase for position five
containing a fyve finger domain), based
on the subsequent characterization of its kinase
activity towards phosphoinositides and other
features. PIKfyve and its products were found to
function as positive regulators of insulin
responsiveness. Since then, the multifaceted
role of PIKfyve and its associated proteins in
phosphoinositide metabolism and cellular
functions has become the major focus of Dr.
Shisheva’s research.

PIKfyve is an
essential component of the mammalian cell
endocytic machinery that binds to membrane
phosphatidyl inositol (PI) 3P (3-phosphate)
and synthesizes PI3,5P2 and PI5P.
PIKfyve mutants defective in PI3,5P2
synthesis or PIKfyve protein ablation cause
enormous cytoplasmic vacuoles. More recent
studies reveal that PIKfyve delivers its
action in a complex with two other protein
partners: ArPIKfyve and Sac3. ArPIKfyve
activates PIKfyve lipid kinase activity
whereas Sac3 is a lipid phosphatase using
PI3,5P2 as a substrate. Thus
PIKfyve appears to be a part of a molecular
machine synthesizing and turning over PI3,5P2, thereby
regulating endosomal traffic.

Dr. Shisheva’s
findings have attracted a lot of scientific
interest. In addition to confirming her
observations at cellular level, work by
others has established that PIKfyve and Sac3
mutations are associated with human genetic
disorders (Francois-Neetens
Mouchetee fleck corneal dystrophy and
Charcot-Marie-Tooth neuropathy,
respectively). In multicellular model
organisms knockout of PIKfyve is lethal,
whereas mouse knockouts of ArPIKfyve and
Sac3 result in similar neurodegeneration and
early postnatal death. Finally, PIKfyve
ablation inhibits HIV propagation, further
supporting its essential role in endocytic
functions. You could read Dr. Shisheva’s
most recent reviews on the functionality of
PIKfyve and associated proteins
here and
here.

These
observations underscore the importance of
fundamental advances in the field and the
expectaitons that further studies may
provide targets for diagnosis and treatment
of human disease.

Dr. Shisheva's research is supported by NIH and ADA.

Publications

A list of Dr.
Shisheva's peer reviewed publications and
review articles can be found at
PubMed-Shisheva